Neurochemical and cognitive aftermaths of surgery - studies on short- and long-term effects of surgery and anesthesia

Abstract: Background: Each year, around the world, more than 230 million patients have surgery. Improvements in healthcare have resulted in older and sicker patients undergoing surgical interventions. As a result, surgical safety has be-come a global public-health concern. Cognitive impairment has emerged as the most common postoperative complication in these older individuals. The etiology of this condition is unknown, although episodes of hypooxygena-tion/hypoperfusion, negative impacts of anesthetic drugs, cerebral microem-boli from cardiopulmonary bypass during cardiac surgery, and neuroinflamma-tion have been implicated. Aims: To explore the mechanisms behind this postoperative cognitive dys-function, we focused on the impacts of surgery on: 1) blood-brain barrier (BBB) function; 2) changes in the levels of systemic and neuroinflammatory biomarkers; and 3) biochemical evidence of perioperative neuronal damage. We also evaluated whether an unfavorable late neurocognitive postoperative outcome was associated with an enhanced neuroinflammatory response or cerebral biomarker evidence of neuronal injury. Finally, we investigated wheth-er a single perioperative dose of methylprednisolone attenuates the postopera-tive BBB dysfunction and prevents neuroinflammation after cardiac surgery. Methods: We conducted a prospective, observational, two-center study with patients who were undergoing elective major orthopedic surgery. Cognitive function was evaluated preoperatively, at discharge, and at 3 months postop-eratively. Biochemical markers of inflammation, neuronal damage, brain amy-loidosis, and BBB function were measured in cerebrospinal fluid (CSF) and blood samples during the initial 48 hours postoperatively. Furthermore, in a prospective, randomized, double-blinded, double-armed study, 30 patients who were undergoing elective open heart surgery were randomized to a single dose of either methylprednisolone or placebo. CSF and blood samples ob-tained preoperatively and at 24 hours after surgery were analyzed for biochem-ical markers of inflammation, neuronal damage, and BBB function. Results: Disruption of BBB function, manifested as an increased CSF to serum albumin quotient, was detected after both cardiac and orthopedic sur-geries. Both orthopedic and cardiac surgeries were associated with a pro-nounced increase in inflammatory biomarkers in the CSF and blood. The CSF inflammatory biomarkers were significantly associated with long-term cogni-tive decline 3 months after orthopedic surgery. . Surgery resulted in increased levels of biomarkers of neuronal damage and brain amyloidosis in the CSF and blood, although there was no association between these biomarkers and postoperative cognitive decline. None of preoperative bi-omarkers were predictive of postoperative cognitive decline. Methylprednisolone attenuated the systemic inflammatory reaction but not the BBB dysfunction that followed cardiac surgery. Conclusions: Surgery induces a profound systemic inflammatory reaction, fol-lowed by disruption of the BBB. Single-dose treatment with a potent corticosteroid did not attenuate the BBB disruption. The postoperative neuroinflammatory reac-tion, assessed as biomarker levels in the CSF, is significantly associated with long-term cognitive decline, whereas the increased postoperative markers of neuronal damage showed no such association